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Shu-Hua Wang, MD, MPH &TMAssistant Professor of Medicine

The Ohio State University

For anti-tuberculosis medications: Describe clinical monitoring for adverse drug reactions Case Reviews Nursing interventions and medical management

Review specific drug side effects Review adverse drug reactions

Ongoing Process Initial assessment – nurse/physician Identify high risk individuals Check baseline labs

Staff and Patient education Staff and Patient education Aware of adverse drug reactions Instruct patient to report signs or symptoms

Rash Decrease appetite, nausea, vomiting, abdominal

pain Fatigue or weakness Dark urine Persistent numbness in hands or feet

Document, document, document! EncountersMonthly refill visits Rationale for treatment Adherence with therapy Symptoms of adverse drug reaction Symptoms of adverse drug reaction Commitment to continue therapy Limited # doses of medication dispensed

DOT visits Case management Assessment/PLAN in placeGood communication with team: MD, RN, MA,

DIS

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Mild reactions

No lasting effect

Usually do not require change in TB meds

Discoloration of body fluid

Gas, bloating, mild nausea

Itching, mild rash

Photosensitivity

Sleep disturbances

Headache

Serious

May be life threatening

Require change in

Significant nausea, vomiting, diarrhea

Hepatotoxiciy Toxic skin / systemic

reactionsmedication

May require hospitalization

Hearing loss Kidney failure Vision loss Hematologic reactions Electrolyte

abnormalities Neurologic damage Death

Isoniazid (INH)

Rifampin (RIF)

Pyrazinamide (PZA)

Ethambutol (EMB)

First-Line Drugs Second-Line Drugs

Streptomycin

Cycloserine

p-Aminosalicylic acid

Ethionamide

Amikacin or kanamycin*

Capreomycin

Levofloxacin*

Moxifloxacin*

Linezolid*

** Not approved FDA for TB TreatmentNot approved FDA for TB Treatment

Rifampin1966

Isoniazid1952

Ethambutol1961

Pyrazinamide1952

Vitamin B6

Drug Adverse Reaction

Signs and Symptoms

Any drug Allergy Skin rash

Ethambutol Eye damage Blurred or changed visionChanged color vision

Isoniazid Hepatitis Abdominal painIsoniazid,Pyrazinamide,orRifampin

Hepatitis Abdominal painAbnormal liver function test resultsFatigueLack of appetiteNauseaVomitingYellowish skin or eyesDark urine

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Drug Adverse Reaction

Signs and Symptoms

Isoniazid Peripheral neuropathy

Tingling sensation in hands and feet

Pyrazinamide Gastrointestinalintolerance

Upset stomach, vomiting, lack of appetiteintolerance

Arthralgia

Arthritis

lack of appetite

Joint aches

Gout (rare)Streptomycin Ear damage

Kidney damage

Balance problems

Hearing loss

Ringing in the ears

Abnormal kidney function test results

Drug Adverse Reaction

Signs and Symptoms

Rifamycins

Rifabutin

Thrombocytopenia Easy bruising

Slow blood clotting

Rifapentine

Rifampin

Gastrointestinal intolerance

Drug interactions

Upset stomach

Interferes with certain medications, such as birth control pills, birth control implants, and methadone treatment

44 year-old maleDiagnosed with active pulmonary TB disease TST Positive Abnormal CXR Smear positive NAA test positive for M.tb Culture pending

Started on 4 drug anti-TB medications RIF, INH, PZA, and EMB

Seen in clinic 2 weeks after starting meds with nausea

GI reactions are common

Especially in the first few weeks of therapy

Many anti-TB meds cause GI upset

Check AST and bilirubin

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Check

AST/ALT + Bili

AST/ALT

< 3 X ULN

Assume symptoms not due to hepatotoxicity

AST/ALT

>=3 X ULN

Hepatotoxicity

Not due to hepatotoxicity

(AST/ALT < 3 X ULN)

Directly observed therapy

1.

Change the time of DOT

2.

Take meds close

to meals

3.

Take meds with food

Self-administeredtherapy

1.

Take meds at bedtime

2.

Take meds with meals

34 year-old female TB suspect TST positive Joint pain in elbow X 3months with swelling Surgical I&D (incision and drainage)Surgical I&D (incision and drainage) AFB smear negative NAA test - pending Culture pending

Started on 4 drug anti-TB medications RIF, INH, PZA, and EMB

Seen in clinic one week after starting meds with complaints of rash

Insect bites, scabies

Contact dermatitis New soap, detergent,

lotions perfumes

Where is it? Where did it start? Where has it spread to?

What does it look lotions, perfumes

Sunburn

Dry skin

Other drugs –new

Other infections

like? What makes it better or worse?

When did it start?

Who has it?

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All drugs used in treating TB can cause rash

Rash is minor – Affecting limited area Affecting limited area Predominantly itching

Antihistamine Symptomatic relief

Continue anti-TB medications

Localized itching without erythematous rashis common early side effect

If patient is taking RIF

Check platelet Check platelet count

If platelet count is low, presume RIF hypersensitivity

RIF should be stopped and the platelet count monitored until it returns to

baseline

RIF should not be restarted

Wikepedia

Stop all drugs immediately Especially if associated with fever

and/or mucous membrane involvement

If ti t h TB th If patient has severe TB, three new drugs should be started aminoglyocoside and two oral agents

Rash is substantially improved Restart medication one by one, Add new drug every 2 – 3 days

http://www.japi.org/june_2011/article_15.html

RIF should be restarted first Least likely to cause rash Most important agent

Followed by INH Followed by EMB or PZA Followed by EMB or PZA If the rash recurs stop last drug added If no rash appears after the first three drugs

have been restarted continue first 3 drugsCan add fourth drug if… If the rash was relatively mild and If the fourth drug is considered essential therapy.

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29 year-old maleDiagnosed with active pulmonary TB disease Sputum AFB smear and culture positive

Started on anti-TB medications Cough and fever resolved sputum converted Cough and fever resolved, sputum converted

AFB smear negative, returned to work Seen in clinic 6 weeks after TB meds start Complaints of fever: Comes and goes Physical Examination Temp >400C, BP 120/60, HR 100, RR 18 No acute distress, normal examination

Recurrence of fever in a patient who has been receiving therapy for several weeks Especially if the patient is showing microbiological

and radiographic improvement

Fever from TB may persist for as long as 2 th ft th h b i iti t dmonths after therapy has been initiated

Fever can be a paradoxical reaction Especially in patient with HIV infection

Patient looks and feels well despite Temp >390CNo specific pattern to the fever Eosinophilia may or may not be present

Ensure there is no superinfection or worsening of TB. Check labs, etc…

Once potential causes are excluded Stop all drugs

Drug-related fever usually resolve within 24 hours

Patients with severe TB should be given at least 3 new drugs (i.e., aminoglyocoside and two oral agents)

Once the fever has resolved, medication can be restarted one by one, at intervals of 2 – 3 days

If fever recurs, the last drug added should be stopped

42 year-old female diagnosed with active TB disease

Smear positive, PCR positive for M.tb Started on 4 drug therapy (RIF, INH, EMB,

PZA)PZA) Baseline labs:

AST-22, ALT-30, T. bili-0.2, Alk phos-45

Seen in clinic after one month AFB smear negative, culture pendingNo complaints, feeling better Repeat ALT 220, AST 98

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Hold all meds

and check LFTs

No symptoms No symptoms Symptomatic and

LFTs <= 5X ULN

Continue therapy

and

ALT > 5X ULN

STOP therapy

and

ALT >3X ULN

STOP therapy

Asymptomatic ALT increase in ~20% of patient

Clinical hepatitis 0.1-0.6% Timing: weeks to months of starting drug Risk factors: Risk factors: Age Chronic alcohol consumption Active hepatitis B (+HBeAg) Elevated baseline transaminases (AST, ALT) Concomitant use of other hepatotoxic drugs 3rd trimester pregnancy to 3 months post-partum Pre-existing liver disease

AJRCCM, 2006; 174:935-952

Serologic testing Hepatitis A, B, C Ask patient symptoms of biliary tract disease Exposure to other hepatotoxins Alcohol Other drugs (RX and OTC)

HepatitisHepatitis No symptoms but LFT > 5X ULN or Symptoms and LFT > 3 X ULN

Start at least 3 nonhepatotoxic drugs Slower schedule for restarting anti-TB medication

compared to rash or drug fever EMB, FQ, strep/amikacin, (capreomycin, cycloserine)

Monitor Labs

When to restart therapy (RIF, INH, PZA) LFTs < 2 X ULN or baseline (abnormal prior to TB meds)

Re-challenge medications One drug at a time Start with RIF Recheck AST after one week No increase

Add INHAdd INH Recheck AST after one week No increase

Add PZA* If symptoms recur or AST increases stop last drug added

*If RIF and INH are tolerated, and hepatitis was severe Do not add back PZA - assumed PZA was responsible

Once added back RIF, INH, + PZA Continue EMB and stop other “liver friendly” drugs added

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Dose related, uncommon

Risk factors Other conditions with neuropathy: Malnutrition, diabetes, HIV, renal failure, alcohol,

pregnant femalep g

Mild peripheral neuritis - Stocking glove syndrome ~2%

Retrobulbar (optic) neurititis

CNS toxicity: Slurred speech, ataxia, seizure, memory

Pyridoxine INH

http://en.wikipedia.org/wiki/Isoniazidhttp://en.wikipedia.org/wiki/Pyridoxine

Orange discoloration of body fluid

Cutaneous reactions: Mild Generally self-limited Treat symptomatically - antihistamine

Gastrointestinal symptoms: Nausea, anorexia, abdominal pain

Hepatocellular injury less common Insidious cholestasis Anorexia, nausea, vomiting, fever, jaundice

RIF is much less likely to cause hepatoxicity than INH or PZA

http://connect.in.com/thrombocytopenia/photo-gallery-more.html

Flu-like syndrome with fever, chills, headache, & bone pain◦ Can begin 1-2 hrs after medication dose and resolve

spontaneously after 6-8 hrs◦ More common in intermittent dosing higher doseMore common in intermittent dosing, higher dose◦ Can try daily therapy if mild

Severe immunologic reactions – rare, each < 0.1% patients◦ Low platelet count / petechiae◦ Kidney dysfunction◦ Hemolytic anemia◦ Thrombotic thrombocytopenic purpura

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Rifampin induces cytochrome P450 class of enzymes Involved in drug metabolism

Rifampin interacts with Narcotics (methadone) Narcotics (methadone) - Corticosteroids – Warfarin (coumadin) – Phenytoin (dilantin) – Contraceptives (estrogens) - HIV protease inhibitors & non-nucleoside reverse

transcriptase inhibitors – complex interactions

Hepatotoxicity: Both dose-dependent & idiosyncratic

Causes hepatotoxicity less often than INH but Can be more prolonged Can continue after drug discontinued Can be most severe

Can cause granulomatous hepatitis Fever, rash, lymphadenopathy, elevated ALT

Gastrointestinal symptoms: nausea, vomiting Arthralgias common – Rx symptomatically Elevated uric acid◦ PZA is a pro-drug active compound Pyrazinoic acid Blocks renal tubular excretion of uric acid Increase uric acid

◦ Allopurinol does not reverse this◦ Routine measurement of uric acid is not

recommended◦ Gout is rare◦ Hyperuricemia without gout is not a reason for

discontinuing drug

Retrobulbar neuritis: decrease visual acuity or red-green color discrimination

Increase risk with renal insufficiency Peripheral neuritisCutaneous reactions: <1% Joint pain

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Baseline and monthly Visual acuity test

(Snellen chart)

Color discrimination test (Ishihara tests)

Patient education

Monthly symptom check blurred vision etc

Opthalmologyevaluaion

Hold medication – for any symptoms

Arthralgias, tendonitis, tendon rupture –very rare All ages Greater risk age >60

P i ki i id Patients taking corticosteroids Transplant patients

EKG abnormalities: QT prolongationNausea & diarrhea: 0.5-2% Rash/Pruritis/Photosensitivity: 0.2-0.4% Avoid in pregnancy

OtotoxicityVestibular toxicityNephrotoxicity Electrolyte disturbancesy Potassium, calcium, and magnesium depletion Cardiac dysrhythmias

Local pain at IM injection site Avoid in pregnancy

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Itching with or without erythematous rash is common early side effect May resolve after 1st several weeks of therapy

without stopping medicationsFor mild or localized reaction continue For mild or localized reaction, continue treatment & treat the rash and pruritis symptomatically – antihistamines, topical steroids

Photosensitivity PZA, fluoroquinolones

http://emedicine.medscape.com/article/1049648-overview

Hives, urticaria, erythematous rash Any drug Stop all drugs immediately, rechallenge 1 at a

time Wait for rash to resolve Start RIF 1st (least likely to be cause) If no recurrence after 2-3 days start INH Continue with EMB or PZA Discontinue any drug which causes recurrence

Angioedema, anaphylaxis, or airway compromise Stop drug – consider desensitization in ICU

Spectrum of diseases – generalized, involve mucus membranes, cause fever – epidermis separates from dermis Stevens-Johnson Syndrome

T i E id l N l i ( f Toxic Epidermal Necrolysis (severe form SJS)

Mortality highQuinolones Emergency, hospitalization Stop offending drug, do not use again

Improves if drugs are administered with food or closer to bedtime

Ethionamide Causes profound GI symptoms Metallic taste, nausea, vomiting that can be severe, loss of

appetite abdominal painappetite, abdominal pain Dose-related May give as split dose

P-Aminosalicylic Acid (PAS) Significant GI intolerance, less with granular formulation Dose-related

INH Commercial liquid preparations contain sorbitol which can

cause diarrhea

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Numbness, tingling hands & feet in stocking-glove pattern

Risk factors: diabetes, alcoholism, HIV, hypothyroidism, pregnancy, poor nutrition, inadequate dietary intake of pyridoxine

Pyridoxine supplements 10-50 mg daily (should this be routine?) for INH 100-200 for cycloserine &/or ethionamide

INH Dose-related Interferes with biologic function of vitamin B6

Ethionamide Increased incidence with prolonged use

Linezolid Increased incidence with prolonged use 600 mg daily instead of twice daily is used to

prevent this

Ethambutol, cycloserine Rare

INH Inability to concentrate, irritability, dysarthria,

seizures, dysphoria

Cycloserine (Dr K’s mnemonic – cyclo, psycho) Headache, restlessness, psychosis, seizures (dose-Headache, restlessness, psychosis, seizures (dose

related) Pyridoxine 100-200 mg daily to prevent / treat

Ethionamide Anxiety, depression, psychosis Increased incidence with prolonged treatment

Fluoroquinolones Dizziness, insomnia, tremulousness, headache

Ethambutol Retrobulbar neuritis Dose related – very rare (if at all) with currently

recommended doses Decreased red green color discrimination (1 or Decreased red-green color discrimination (1 or both eyes), decreased visual acuity

With renal disease

Ethionamide Optic neuritis Dose related

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Streptomycin Vestibular (balance) and hearing disturbance Related to single dose size and cumulative dose

(>100-200 g)Increased with incidence if diuretics are used Increased with incidence if diuretics are used

Monitor with audiogram, Romberg Hearing loss can be permanent – consider

stopping

Amikacin & Kanamycin Less vestibular toxicity than SM

Capreomycin These drugs also cause nephrotoxicity & require monitoring

Injectable agents – 15mg/kg daily or 25 mg/kg TIW Ototoxicity often permanent *Hearing loss > 20 db occurred in 32/87 (37%)

patients, 88% had persistent loss at end of follow upfollow-up

Associated with older age, duration of treatment, & total dose, not to vestibular or renal toxicity

Amikacin>Kanamycin >Streptomycin TIW = daily Rx

*Peloquin, et al. Aminoglycoside toxicity…Clin Inf Dis 2004;38:1538-44

Acknowledgement: Special thanks to Dr. Dana Kissner , Wayne State University

44 year old female diagnosed with latent TB infection

8/3 seen by physician and nurse Started INH Baseline labs:

AST 19 ALT 19 T bili 0 3 Alk h 68 AST-19, ALT-19, T. bili-0.3, Alk phos-68

9/1 - Nurse Refill Visit #2 Repeat AST on 09/01 was 27

10/6 - Nurse Refill Visit #3 11/10 – Nurse Refill Visit #4 11/30 admitted for “jaundice”

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No signs or symptoms of any hepatic problems reported at any health dept visits

2 weeks prior to admission – ER visit – cough CXR negative Tessalon® perles and hydrocodone cough syrupTessalon perles and hydrocodone cough syrup

Increasing fatigue, weakness, diarrhea, yellowing of eyes

Return to hospital AST-36271410 ALT 21591621 Alk phos 190179 Total Bili 2527.5 (Direct 1316.6)

RUQ ultrasound: no intrahepatic ductal dilation, + cholelithiasis, no cholecystitis, no liver abnormalities

Abdominal MRI: no biliary ductal dilation, no ll t li l igallstones, no liver lesions

Liver biopsy: patchy hepatocellular necrosis with acute and chronic inflammation. mild portal fibrosis, no granuloma/viral inclusions

Diagnosis: Acute Hepatitis- secondary to INH toxicity

Slide courtesy of Dr Jonathon Rock and OSUMC Clinical Pathology Slide courtesy of Dr Jonathon Rock and OSUMC Clinical Pathology

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Adult median age 39

MMWR 3/5/10 59(08); 224-229

Dx 2nd and 9th

month

HIV, Hep C

AST

ALT

MMWR 3/5/10 59(08); 224-229

Idiosyncratic reaction, independent of dosing Can occur anytime in treatment 9/17 beyond the 3rd month

Can occur in children 2/17 in children

Diagnosed not by prescribing physician 10/17

Did NOT STOP the medication when symptoms developed 8/17 continue to take the medication

MMWR 3/5/10 59(08); 224-229http://en.wikipedia.org/wiki/Jaundice

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•PPV 99.76%

•Annual risk of developing TB=0.1%

•Cumulative risk of active TB disease up to age 80 is 5.19%

•If treated with INH probability of significant drug induced hepatitis is 0.3%

•Association with probability of hospitalized drug induced hepatitis is 0.1%

25 year old female diagnosed with lymph node TB started on four drug: RIF, INH, EMB, PZA On day 8: developed generalized

papulosquamous rashes involving both thighs, l t k f d l it legs, trunk, face and oral cavity

She was admitted outside and was put on antibiotics along with steroids

Patient improved slightly, was discharged after 5 days. TB meds were continued

http://www.japi.org/june_2011/article_15.html

4-5 days later patient again developed increase generalized body rashes

Febrile, vitals –stable

Treated with steroids and TB medication discontinued

Fig. 2 : Clinical photographs showing multiple areas of erosions over the hands and feet with thick adherent yellow crusts, some showing whitish scales, hyperpigmentation along with thick dystrophic nails

http://www.japi.org/june_2011/article_15.html

RIF INH PZA EMB

Rash

GI Intolerance

Liver toxicity

Place a check mark for the common side effects

Peripheral Neuropathy

Optic Neuritis

Gout

Discolorationof body fluid

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RIF INH PZA EMB

Rash X X X XGI Intolerance X X X XLiver toxicity X X XPeripheral Neuropathy X

Optic Neuritis X (rare) XGout X X (rare)

Discolorationof body fluid X

Gastrointestinal Effects – severe May improve with food or at bedtime

Hepatotoxicity: 2%Neurotoxicity: peripheral neuropathy, optic

neuritis, depression, psychosis Endocrine disturbances Gynecomastia, hair loss, hypothroidism, impotence Diabetes may be more difficult to manage Acne Irregular menstrual cycles

Nausea & diarrheaMyelosuppression Dose dependent Reversable

Peripheral neuropathy Not dose dependent May not be reversible

Optic neuritis Serotonin syndrome Rash

Gatrointestinal distress: 11%, dose/stop medHypothyroidism is common Reversible, with ethionamide Goiter can develop

Hepatitis: 0.3%Malabsorption - fat malabsorption Doubling of prothrombin time Vitamin K is a fat soluble vitamin

Levels of fat soluble vitamins (A, D, E) can be measured & monitored

Rash, lymphadenopathy, leukocytosis, arthralgia

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Central nervous system effects: headaches, restlessness, suicidal ideation, psychosis, seizures (3% 500mg/day)

Caution in patients with underlying seizure di d t l illdisorders or mental illness

Pyridoxine 100-200mg/day may decrease neurotoxic side effect

Peripheral neuropathy Rash – skin changes (lichenoid eruptions,

Stevens-Johnson Syndrome)